The amyloid concentric β-barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels.
The amyloid concentric β-barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels.
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作者：
Durell SR;Guy HR
淀粉样β蛋白(阿尔茨海默病的一种β)和α-突触核蛋白(帕金森氏病的α-Syn)形成大的纤维。然而，越来越多的证据表明，小得多的低聚物毒性更大，而且这些低聚物可以形成跨膜离子通道。我们以前曾提出Aβ42低聚物、环状原纤维和离子通道采用同心β-Barrel分子结构。在这里，我们将这一假设扩展到α，β超家族和γ-突触核蛋白。我们开发的大量突触核蛋白低聚物、环状原纤维、管状原纤维、脂蛋白和离子通道的模型与EM和其他研究确定的组件的大小、形状、相对分子质量和二级结构一致。该模型具有以下特点：1)所有亚基具有相同的结构和相互作用；2)它们与传统的β-Barrel理论一致；3)相邻β-Barrel的壁距在0.6~1.2 nm之间；4)氢键、盐桥、芳香族侧链之间的相互作用、疏水侧链的埋藏和紧密堆积以及亲水性侧链的水溶液暴露是相对最优的；5)大多数低聚物内部的远亲同源蛋白簇之间的残基相同，而高度可变的残基暴露在蛋白质表面。建立了一些组件的原子尺度模型。
Amyloid beta (Aβ of Alzheimer’s disease) and α-synuclein (α-Syn of Parkinson’s disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aβ42 oligomers, annular protofibrils, and ion channels adopt concentric β-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, β, and γ-synucleins. Our models of numerous Synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by EM and other studies. The models have the following features: 1) all subunits have identical structures and interactions; 2) they are consistent with conventional β-barrel theory; 3) the distance between walls of adjacent β-barrels is between 0.6 and 1.2 nm; 4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and 5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.
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α-突触核蛋白寡聚物在帕金森病中的作用。
影响因子：
5.6
作者：
Du XY;Xie XX;Liu RT
通讯作者：
Liu RT
影响因子：
15
作者：
Do TD;LaPointe NE;Nelson R;Krotee P;Hayden EY;Ulrich B;Quan S;Feinstein SC;Teplow DB;Eisenberg D;Shea JE;Bowers MT
通讯作者：
Bowers MT
DOI：
10.1126/science.aao2825
发表时间：
2017-10-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gremer L;Schölzel D;Schenk C;Reinartz E;Labahn J;Ravelli RBG;Tusche M;Lopez-Iglesias C;Hoyer W;Heise H;Willbold D;Schröder GF
通讯作者：
Schröder GF
DOI：
10.1073/pnas.1421204112
发表时间：
2015-04-21
影响因子：
11.1
作者：
Chen, Serene W.;Drakulic, Srdja;Cremades, Nunilo
通讯作者：
Cremades, Nunilo
影响因子：
3.5
作者：
Eichmann, Cedric;Kumari, Pratibha;Riek, Roland
通讯作者：
Riek, Roland